Oxidative reactions monoamine oxidases

The reactions presented here must not be confused with oxidative reactions that increase bond order and are catalyzed by oxidoreductases, as discussed elsewhere. Examples of the latter reactions include the cytochrome P450 mediated oxidation of testosterone to 6,7-dehydrotestosterone, and the oxidation of l,2,3,6-tetrahydro-l-methyl-4-phenylpyridine to 2,3-dihydro-1-methy 1-4-phenylpyridinium catalyzed by monoamine oxidase (Chapt. 4 and 9 in [50]). 

This group of enzymes catalyzes the oxidation of amines. Amine oxidase [EC 1.4.3.4], a flavin-containing enzyme (also known as monoamine oxidase, tyramine oxidase, tyraminase, or adrenalin oxidase) catalyzes the reaction of an organic amine R—CH2—NH2) with dioxygen... 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson s Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine 0-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines. 

Deamination. Amine groups can be removed oxidatively via a deamination reaction, which may be catalyzed by cytochromes P-450. Other enzymes, such as monoamine oxidases, may also be involved in deamination reactions (see below). The product of deamination of a primary amine is the corresponding ketone. For example, amphetamine is metabolized in the rabbit to phenylacetone (Fig. 4.27). The mechanism probably involves oxidation of the carbon atom to yield a carbinolamine, which can rearrange to the ketone with loss of ammonia. Alternatively, the reaction may proceed via phenylacetoneoxime, which has been isolated as a metabolite and for which there are several possible routes of formation. The phenylacetoneoxime is hydrolyzed to phenylacetone. Also N-hydroxylation of amphetamine may take place and give rise to phenylacetone as a metabolite. This illustrates that there may be several routes to a particular metabolite. 

Degradation of catecholamines The catecholamines are inacti vated by oxidative deamination catalyzed by monoamine oxidase (MAO), and by O-methylation carried out by catechol-O-methyl-transferase (COMT, Figure 21.15). The two reactions can occur in either order. The aldehyde products of the MAO reaction are axi dized to the corresponding acids. The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 

Using structures, write the reaction for the monoamine oxidase-catalyzed oxidation of benzylamine. 

Monoamine oxidase, tyrosine hydroxylase, and L-amino acid oxidase generate hydrogen peroxide as their reaction product. Hydrogen peroxide is also produced by auto-oxidation of catecholamines in the presence of vitamin C. Moreover, phospholipase A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX), the enzymes associated with arachidonic acid release and the arachidonic acid cascade,... 

Studies with various subcellular fractions are useful to ascertain which enzyme systems are involved in the metabolism of a chug candidate. In the absence of added cofactors, oxidative reactions such as oxidative deamination that are supported by mitochondria or by Ever microsomes contaminated with mitochondria membranes (as is the case with microsomes prepared from frozen liver samples) are likely catalyzed by monoamine oxidase (MAO), whereas oxidative reactions supported by cytosol are likely catalyzed by aldehyde oxidase and/or xanthine oxidase (a possible role for these enzymes in the metabolism of... 

Superoxide is also a product of various enzyme reactions catalyzed by the flavin oxidases (e.g., xanthine oxidase and monoamine oxidase). In addition, 07 is a product of the noncatalytic oxidation of oxyhemoglobin, of which about 3% is converted each day to methemoglobin. Moreover, 02 is readily formed in phagocytic cells (i.e., neutrophils and monocytes) during the respiratory burst. Furthermore, in addition to the Fenton reaction, the Haber-Weiss reaction results in the conversion of 02 to the potent HO via the following reactions (H3) ... 

Disposition in the Body. Rapidly metabolised before reaching the systemic circulation and therefore ineffective after oral administration poorly absorbed after subcutaneous injection widely distributed throughout the body. The principal metabolic reaction is 0-methylation catalysed by catechol-O-methyltrans-ferase to form normetanephrine this is followed by oxidative deamination catalysed by monoamine oxidase, to form 4-hydroxy-3-methoxymandelic aldehyde which is converted to 4-hydroxy-3-methoxymandelic acid (vanillylmandelic acid) and to... 

FIGURE 5. Proposed reaction mechanisms for flavin-catalysed oxidation of amines. A, the carbanion mechanism initially proposed for TMADH (Rohlfs and Hille, 1994). B, the amminium cation radical mechanism, as originally proposed for monoamine oxidase (Silver-man, 1995) although only the pathway passing through a transient covalent intermediate is shown, several alternative pathways for breakdown of the initial flavin semiquinone/... 

Electron-transfer reactions of amines are of significant importance in biochemical systems. Enzymes known to catalyze the oxidative dealkylation of amines include monoamine oxidase [16, 17], cytochrome-P450 [18, 184-186], horseradish peroxidase [187], hemoproteins [188, 189], and chloroperoxidase [187, 188]. N-dealkylation of amines by peroxidases are generally accepted to occur via one-electron transfer, whereas the role of electron transfer in reactions catalyzed by enzymes such as monoamine oxidase [16, 17] and cytochrome P-450 [18, 184, 185] is currently a topic of debate. 

In neuronal function ROS play a role of metabolites immediately participating in the excitation process. In the intracellular space there are both enzymic (cyclooxygenases, monoamine oxidases) and non-enzymic (spontaneous oxidation of biogenic amines) reactions where they are formed. Mitochondrial respiratory chain also provides ROS production in a cell under conditions of changeable oxygen pressure [29,30]. 

Of the Phase I reactions, oxidative biotransformations are by far the most common. These reactions are carried out by several oxidative enzyme systems, the most predominant of which is the CYP superfamily of enzymes. Additional oxidative enzymes include FMO, xanthine oxidase, aldehyde oxidase, alcohol and aldehyde dehydrogenases monoamine oxidases, and various peroxidases. Determining the enzyme(s) employed to biotransform any particular substrate will depend on the substrates chemical and physical characteristics as well as functional substituents. This chapter does not describe in detail the mechanism of these various enzymes however, it does illustrate the product(s) (i.e., metabolites) produced by each reaction. 

Oxidative biotransformations, which constitutes the major portion of Phase I reactions, can be catalyzed by either cytochrome P450s (CYP450) or nonmicrosomal enzymes such as flavin-containing monooxygenases (FMOs), monoamine oxidase (MAOs), alcohol dehydrogenase, and aldehyde dehydrogenase. As listed in Table 5.1,... 

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